Hydroxyl group reactions halogens

The reaction is quite susceptible to steric effects since hindered secondary hydroxyl groups were found to be unreactive. The method can therefore be used to selectively replace a primary hydroxyl group by halogen in the presence of more hindered secondary hydroxyl groups in the same molecule. An example (70) is the reaction of 52 with triphenylphosphite methiodide which affords the 6-deoxy-6-iodo derivative 53 (60%) in which the C-2 hydroxyl group remains intact. 

In contrast to uridine,389 cytidine does not yield a 5 -chloro-5 -deoxy derivative on reaction with N,N-dimethyl(chlorometh-animinium) chloride instead 2,2 -anhydrocytidine is formed.395 However, thionyl chloride or bromide in hexamethylphosphor-amide at room temperature achieves this selective replacement of the primary hydroxyl group of halogen in cytidine, and also in adenosine, in respective yields of 80 and 75% for the chloro compounds, and 55 and 30% for the bromo analogs.396... 

The hydroxyl of a COOH-group may be replaced by chlorine by means of reactions, in part similar to that described above for the replacement of alcoholic hydroxyl groups by halogen. 

The reaction between silica and halogenating reagents permits the direct replacement of hydroxyl groups with halogen atoms, yielding reactive =Si-X surface groups. 

Here, the amino group has provided the extra electrons, i.e. it has acted as an electron source. A hydroxyl group or halogen atom may act in a similar manner to the amino group. If an electron source and an electron sink are conjugated together, then a permanent dipole may be formed as a result of the mesomeric redistribution of the 7i electrons. This type of scheme can be characterised as a push-me, pull-you system, and is often instrumental in initiating reactions. 

The Pd-catalyzed oxidation of unfunctionalized C-H bonds has recently been described by Sanford. These reactions lead to the direct, regioselective installation of hydroxyl groups or halogen atoms onto aromatic and heteroaromatic ring systems. For example, benzo[//]quinoline is selectively converted to 10-chlorobenzo[A]quinoline upon treatment with catalytic Pd(OAc)2 and NCS [103]. As shown below, these transformations are also effective for the installation of oxygenated functional groups including acetates and alkyl ethers. The oxidative functionalization of. sy/ C-H bonds has also been achieved [104]. 

Over the last decade, a considerable number of reactions has been studied (11,35) (i) olefins oxidation (38,39), hydroboration, and halogenation (40) (ii) amines silylation (41,42), amidation (43), and imine formation (44) (iii) hydroxyl groups reaction with anhydrides (45), isocyanates (46), epichloro-hydrin and chlorosilanes (47) (iv) carboxylic acids formation of acid chlorides (48), mixed anhydrides (49) and activated esters (50) (v) carboxylic esters reduction and hydrolysis (51) (vi) aldehydes imine formation (52) (vii) epoxides reactions with amines (55), glycols (54) and carboxyl-terminated polymers (55). A list of all the major classes of reactions on SAMs plus relevant examples are discussed comprehensively elsewhere (//). The following sections will provide a more detailed look at reactions with some of the common functional SAMs, i.e hydroxyl and carboxyl terminated SAMs. 

A variety of terminal functional groups and their chemical transformations on SAMs have been examined for example, (i) olefins—oxidation [23,24,131,132], hydroboration, and halogenation [23,24] (ii) amines—silyla-tion [145,146], coupling with carboxylic acids [22,146], and condensation with aldehydes [22,147] (iii) hydroxyl groups—reactions with anhydrides [148,149], isocyanates [150], epichlorohydrin [151], and chlorosilanes [152] (iv) carboxylic acids—formation of acyl chlorides [153], mixed anhydrides [154], and activated esters [148,155] (v) carboxylic esters—reduction and hydrolysis [156] (vi) thiols and sulfides—oxidation to generate disulfides [157-159] and sulfoxides [160] and (vii) aldehydes—condensation with active amines [161], Nucleophilic... 

The reaction of an alcohol with a hydrogen halide is a substitution A halogen usually chlorine or bromine replaces a hydroxyl group as a substituent on carbon Calling the reaction a substitution tells us the relationship between the organic reactant and its prod uct but does not reveal the mechanism In developing a mechanistic picture for a par ticular reaction we combine some basic principles of chemical reactivity with experi mental observations to deduce the most likely sequence of steps... 

Halogenation. Normally, 2-halopropane derivatives are prepared from isopropyl alcohol most economically by reaction with the corresponding acid haUde. However, under appropriate conditions, other reagents, eg, phosphoms haUdes and elemental halogen, also react by replacement of the hydroxyl group to give the haUde (46). 

Sulfonate Esters. Sucrose sulfonates are valuable intermediates for the synthesis of epoxides and derivatives containing halogens, nitrogen, and sulfur. In addition, the sulfonation reaction has been used to determine the relative reactivity of the hydroxyl groups in sucrose. The general order of reactivity in sucrose toward the esterification reaction is OH-6 OH-6 > OH-1 > HO-2. 

In many cases, substituents linked to a pyrrole, furan or thiophene ring show similar reactivity to those linked to a benzenoid nucleus. This generalization is not true for amino or hydroxyl groups. Hydroxy compounds exist largely, or entirely, in an alternative nonaromatic tautomeric form. Derivatives of this type show little resemblance in their reactions to anilines or phenols. Thienyl- and especially pyrryl- and furyl-methyl halides show enhanced reactivity compared with benzyl halides because the halogen is made more labile by electron release of the type shown below. Hydroxymethyl and aminomethyl groups on heteroaromatic nuclei are activated to nucleophilic attack by a similar effect. 

Hydrazinopyridazines such as hydralazine have a venerable history as anti hypertensive agents. It is of note that this biological activity is maintained in the face of major modifications in the heterocyclic nucleus. The key intermediate keto ester in principle can be obtained by alkylation of the anion of pi peri done 44 with ethyl bromo-acetate. The cyclic acylhydrazone formed on reaction with hydrazine (46) is then oxidized to give the aromatized compound 47. The hydroxyl group is then transformed to chloro by treatment with phosphorus oxychloride (48). Displacement of halogen with hydrazine leads to the formation of endralazine (49). ... 

Thus, reduction of the Mannich reaction product (65) from acetophenone leads to alcohol 66. Replacement of the hydroxyl group by chlorine (67) followed by displacement of halogen with the anion from o-cresol affords the ether 68. Removal of one of the methyl groups on nitrogen by means of the von Braun reaction or its modem equivalent (reaction with alkyl chloroformate followed by saponification) leads to racemic 69 which is then resolved with L-(+)-mandelic acid to give the levorotary antidepressant tomoxetine (69) [16]. 

The hydroxyl group is a strongly activating, ortho- and para-directing substituent in electrophilic aromatic substitution reactions (Section 16.4). As a result, phenols are highly reactive substrates for electrophilic halogenation, nitration, sulfonation, and lTiedel-Crafts reactions. 

We say that the hydroxyl group has been displaced, and the halogen atom substituted for it. You can see that the group CH3CH2— has remained intact in all of these reactions. Indeed, this group has appeared in most of our discussion so far, sometimes attached to oxygen (as in ethanol and sodium ethoxide), sometimes attached to other atoms (as in the ethyl halides). You will recall that earlier we became acquainted... 

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